The major histocompatibility complex (HLA) in man plays an important role in the genetic control of immune responses to foreign histocompatibility antigens. Two in vitro models enable one to study the allograft response; these are the mixed lymphocyte culture (MLC) and the cell-mediated lympholysis (CML) responses. When lymphocytes from individual "A" are cultured with inactivated lymphocytes from individual "B" they recognize foreign histocompatibility determinants expressed by "B". This recognition results in enlargement and division of responding cells. which is measured in MLC; after six days of culture the responding cells acquire the ability to damage cells from "B". This response is measured in CML. Genetic disparity at HLA plays an important role in stimulation of MLC, induction of cytotoxic lymphocytes, and recognition of target cells. Different loci of HLA function in these responses. HLA-D controlled determinants stimulate strong MLC and enhance the development of cytotoxic lymphocytes; determinants controlled by HLA-A, B, and C function in sensitization of cytotoxic lymphocytes and serve as target antigens. Recent studies of our own and others indicate that other determinants, also controlled by genes of the HLA complex, are recognized by cytotoxic lymphocytes. These determinants are not identified by serological techniques which identify the HLA-A, B, and C products; however, they can be identified by CML. The purpose of these studies is to use CML to identify new histocompatibility determinants, to study the specificity of these determinants, and to analyze the genetic system responsible for their expression. Such studies will enable one to further characterize the genetic fine structure of the HLA complex and to investigate its interactions in the control of the allograft response.